LY-379268, -Drug Synthesis Database

【结构式】

【药物名称】LY-379268

【化学名称】(1R,4R,5S,6R)-4-Amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid

【CA登记号】191471-52-0, 191471-50-8 (stereoisomer), 191471-51-9 (stereoisomer)

【分子式】C₇H₉NO₅

【分子量】187.15348

【开发单位】Lilly (Originator)

【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, mglu2 Agonists, mglu3 Agonists

合成路线1 合成路线2 合成路线3

合成路线1

Treatment of 1,2,4-butanetriol (I) with acetone and p-toluenesulfonic acid gave the isopropylidene ketal (II). Subsequent Swern oxidation of the unprotected alcohol group of (II) produced aldehyde (III), which was condensed with phosphorane (IV) to afford unsaturated ester (V). Ketal hydrolysis of (V) gave ethyl 5,6-dihydroxy-2-hexenoate (VI), which was cyclized by means of iodine and NaHCO3 to produce the (tetrahydrofuranyl)-2-iodoacetate (VII). Further oxidation of the hydroxyl group of (VII) by means of Jones reagent yielded iodoketone (VIII). This was cyclized in the presence of DBU to generate the bicyclic compound (IX). The Bucherer-Bergs reac-tion of (IX) with potassium cyanide and ammonium carbonate produced the spiro hydantoin (X). Resolution of (X) was then achieved by ethyl ester hydrolysis, followed by recrystallization of the corresponding diastereomeric salt with (R)-2-phenylglycinol. Basic hydrolysis of the hydantoin ring of the required isomer (XII) then yielded the title compound.

参考文献中间体

【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. US 5688826 .
【2】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. EP 0774461; JP 2000500748; WO 9718199 .
【3】 Levine, L.R. (Eli Lilly and Company); Treatment for premenstrual dysphoric disorder. WO 9832436 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	30088	1,2,4-butanetriol	3068-00-6	C₄H₁₀O₃	详情	详情
(II)	30089	2-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-ethanol		C₇H₁₄O₃	详情	详情
(III)	30090	2-(2,2-dimethyl-1,3-dioxolan-4-yl)acetaldehyde		C₇H₁₂O₃	详情	详情
(IV)	14182	ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane	1099-45-2	C₂₂H₂₁O₂P	详情	详情
(V)	30091	ethyl (E)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-butenoate		C₁₁H₁₈O₄	详情	详情
(VI)	30092	ethyl (E)-5,6-dihydroxy-2-hexenoate		C₈H₁₄O₄	详情	详情
(VII)	30093	ethyl 2-(4-hydroxytetrahydro-2-furanyl)-2-iodoacetate		C₈H₁₃IO₄	详情	详情
(VIII)	30094	ethyl 2-iodo-2-(4-oxotetrahydro-2-furanyl)acetate		C₈H₁₁IO₄	详情	详情
(IX)	30095	ethyl 4-oxo-2-oxabicyclo[3.1.0]hexane-6-carboxylate		C₈H₁₀O₄	详情	详情
(X)	30096	2,5-Dioxospiro[oxazolidine-4,4'-[2]oxaabicyclo[3,1,0]hexane]-6'-carboxylic acid ethyl ester		C₁₀H₁₁NO₆	详情	详情
(XII)	30097	(1'R,4S,5'S,6'S)-2,5-Dioxospiro[imidazolidine-4,4'-[2]oxabicyclo[3,1,0]hexane]-6'-carboxylic acid		C₈H₈N₂O₅	详情	详情

合成路线2

In a related procedure, the chiral triol (XIII) was protected as the ketal (XIV), and then oxidized to aldehyde (XV). Subsequent Wittig condensation of (XV) with phosphorane (IV) afforded unsaturated ester (XVI). After ketal hydrolysis of (XVI), cyclization by means of I2 and NaHCO3 yielded cyclic ether (XVIII). Oxidation of (XVIII) to ketone (XIX) and cyclization in the presence of DBU produced bicyclic compound (XX). This was converted to the chiral spiro hydantoin (XXI) with KCN and (NH4)2CO3 and finally hydrolyzed with NaOH to give the corresponding dicarboxylic acid.

参考文献中间体

【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. US 5688826 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	14182	ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane	1099-45-2	C₂₂H₂₁O₂P	详情	详情
(XIII)	30098	(2S)-1,2,4-butanetriol; (S)-1,2,4-butanetriol	42890-76-6	C₄H₁₀O₃	详情	详情
(XIV)	30099	2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol		C₇H₁₄O₃	详情	详情
(XV)	30100	2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]acetaldehyde		C₇H₁₂O₃	详情	详情
(XVI)	30101	ethyl (E)-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-butenoate		C₁₁H₁₈O₄	详情	详情
(XVII)	30102	ethyl (E,5S)-5,6-dihydroxy-2-hexenoate		C₈H₁₄O₄	详情	详情
(XVIII)	30103	ethyl (2S)-2-[(2R,4S)-4-hydroxytetrahydro-2-furanyl]-2-iodoethanoate		C₈H₁₃IO₄	详情	详情
(XIX)	30104	ethyl (2S)-2-iodo-2-[(2R)-4-oxotetrahydro-2-furanyl]ethanoate		C₈H₁₁IO₄	详情	详情
(XX)	30105	ethyl (1R,5R)-4-oxo-2-oxabicyclo[3.1.0]hexane-6-carboxylate		C₈H₁₀O₄	详情	详情
(XXI)	30106	(1'R,4S,5'S,6'S)-2,5-Dioxospiro[imidazolidine-4,4'-[2]oxabicyclo[3,1,0]hexane]-6'-carboxylic acid ethyl ester		C₁₀H₁₂N₂O₅	详情	详情

合成路线3

Cycloaddition of ethyl diazoacetate to furan (XXII) in the presence of dirhodium tetraacetate gave bicyclic compound (XXIII). Hydroboration of the olefin group of (XXIII) with tert-hexylborane, followed by oxidative treatment with hydrogen peroxide provided alcohol (XXIV), which was oxidized to ketone (IX) under Swern conditions. The title compound was then obtained as above by formation of hydantoin (X), ester hydrolysis, resolution as before, and hydrolysis of the hydantoin.

参考文献中间体

【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. US 5688826 .
【2】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. EP 0774461; JP 2000500748; WO 9718199 .
【3】 Levine, L.R. (Eli Lilly and Company); Treatment for premenstrual dysphoric disorder. WO 9832436 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	30108	(1,1,2-trimethylpropyl)borane	C₆H₁₅B	详情	详情
(IX)	30095	ethyl 4-oxo-2-oxabicyclo[3.1.0]hexane-6-carboxylate	C₈H₁₀O₄	详情	详情
(X)	30110	2,5-Dioxospiro[imidazolidine-4,4'-[2]oxabicyclo[3,1,0]hexane]-6'-carboxylic acid ethyl ester	C₁₀H₁₂N₂O₅	详情	详情
(XXII)	22732	benzhydryl (7R)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₂₃H₂₄N₂O₄S₂	详情	详情
(XXIII)	30107	ethyl 2-oxabicyclo[3.1.0]hex-3-ene-6-carboxylate	C₈H₁₀O₃	详情	详情
(XXIV)	30109	ethyl (4R)-4-hydroxy-2-oxabicyclo[3.1.0]hexane-6-carboxylate	C₈H₁₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)